Exploiting the Inherent Photophysical Properties of the Major Tirapazamine Metabolite in the Development of Profluorescent Substrates for Enzymes That Catalyze the Bioreductive Activation of Hypoxia-Selective Anticancer Prodrugs.
Exploiting the Inherent Photophysical Properties of the Major Tirapazamine Metabolite in the Development of Profluorescent Substrates for Enzymes That Catalyze the Bioreductive Activation of Hypoxia-Selective Anticancer Prodrugs.
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DOI：
10.1021/acs.joc.7b03035
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发表时间：
2018-02
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通讯作者：
Xiulong Shen;Charles H. Laber;Ujjal Sarkar;F. Galazzi;Kevin M. Johnson;Nathaniel G. Mahieu;Roman Hillebrand;T. Fuchs-Knotts;C. Barnes;G. Baker;K. Gates
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作者：
Xiulong Shen;Charles H. Laber;Ujjal Sarkar;F. Galazzi;Kevin M. Johnson;Nathaniel G. Mahieu;Roman Hillebrand;T. Fuchs-Knotts;C. Barnes;G. Baker;K. Gates
低氧选择性细胞毒素(HSCs)寻求利用肿瘤组织的缺氧性质来获得治疗收益。通常，造血干细胞需要单电子生物还原酶激活，如NADPH：细胞色素P450还原酶(CYPOR)。因此，通过开发和实施检测肿瘤组织中相关生物还原酶存在的诊断探针，可以促进HSCs的成功临床部署。这项工作开发了研究得很好的HSC替拉帕胺的类似物(3-氨基-1，2，4-苯并三嗪1，4-二氮氧化物，TPZ)，作为参与HSC生物激活的单电子还原酶的前荧光底物。TPZ或7-氟-TPZ通过单电子还原酶的低氧代谢释放固有的荧光单-N-氧化物代谢物，可作为检测参与HSCs生物激活的酶的指示物、探针、标志物或染料。特别是，这种类型的前荧光化合物可以为基于荧光的生物检测提供基础，帮助识别对HSCs有反应的肿瘤。
Hypoxia-selective cytotoxins (HSCs) seek to exploit the oxygen-poor nature of tumor tissue for therapeutic gain. Typically, HSCs require activation by one-electron bioreductive enzymes such as NADPH:cytochrome P450 reductase (CYPOR). Thus, successful clinical deployment of HSCs may be facilitated by the development and implementation of diagnostic probes that detect the presence of relevant bioreductive enzymes in tumor tissue. The work described here develops analogues of the well-studied HSC tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di- N-oxide, TPZ) as profluorescent substrates of the one-electron reductases involved in bioactivation of HSCs. Hypoxic metabolism of TPZ or 7-fluoro-TPZ by one-electron reductases releases inherently fluorescent mono- N-oxide metabolites that may serve as indicators, probes, markers, or stains for the detection of the enzymes involved in the bioactivation of HSCs. In particular, profluorescent compounds of this type can provide a foundation for fluorescence-based bioassays that help identify tumors responsive to HSCs.